Sclerosis of varicose veins is based on the injection into the veins of liquid sclerosant substances which, by inter alia causing a localised inflammatory reaction, favour the elimination of these abnormal veins. Until recently, sclerotherapy was a technique selected in cases of small and medium calibre varicose veins, those with diameters equal to or greater than 7 mm being treated by surgery. Sclerotherapy and surgery complemented one another but treatment by sclerotherapy continued to be inapplicable to large varicose veins. In these large varicose veins, if a sclerosing liquid was injected, the amount of liquid sclerosant required to fill the entire length of the varicose vein exceeded safe dosage limits at normal sclerosant concentrations, and may be ineffective at the concentrations required to limit the dosage to safe levels. In addition, its concentration in the vein, its homogeneous distribution in the blood, and the time for which it is in contact with the internal walls of the vessel treated were not known.
An injectable microfoam suitable for therapeutic use, on larger veins in particular, has now been developed and is described in EP-A-0656203 and U.S. Pat. No. 5,676,962 (incorporated herein by reference). These patents describe a low-density microfoam produced with a sclerosing substance which, when injected into a vein, displaces blood and ensures that the sclerosing agent contacts the endothelium of the vessel in a known concentration and for a controllable time, achieving sclerosis of the entire segment occupied.
The preparation of such a foam may be carried out with a solution of any sclerosing substance, particularly polidocanol. The method of preparation is to use a small brush attached to a high-speed motor to whip a dilute aqueous solution of the preferred sclerosant to a firm mousse-like consistency in a period of 1-2 minutes under a gas atmosphere containing physiologically acceptable gas mixes. However, this known method requires extemporaneous production of microfoam by the physician, pharmacist or an assistant immediately prior to administration to the patient. Such procedure allows for variation of microfoam sclerosing agent depending upon the person preparing it; microfoam density, gas makeup, bubble size and foam stability all needing attention with respect to the condition being treated.
A solution to this problem is offered in WO 00/72821-A1 (BTG International Limited), incorporated herein by reference, which provides a method and a number of different devices that are capable of producing a uniform injectable microfoam. This microfoam is made with a relatively low concentration of a foamable sclerosing agent and a significant amount of a blood dispersible gas in sterile fashion without volatile liquid propellants or the need for the operator to directly be concerned in the control of its parameters. This application also addresses the perception that large volumes of nitrogen should not unnecessarily be introduced into patients. This is particularly an issue where large vessels are being filled with foam, if air is used as the gas for producing the foam. A preferred form of gas described in WO 00/72821-A1 comprises 50% vol/vol or more oxygen, the remainder being carbon dioxide, or carbon dioxide, nitrogen and trace gases in the proportion found in atmospheric air. Preferably the sclerosing agent is a solution of polidocanol or sodium tetradecyl sulfate in an aqueous carrier, e.g. water, particularly in a saline.
However, the present inventors have identified a potential problem with this formulation, in making the observation that polidocanol, when stored for several months in the presence of oxygen, may slowly decompose. Thus it appears to be undesirable to store polidocanol in a pressurised can in the presence of oxygen, for example as taught in WO 00/72821-A1, as it may result in a reduced shelf life.
One of the specific embodiments described in WO 00/72821-A1 teaches the use of a “bag-on-valve” type aerosol device for the production of a therapeutic microfoam. In this particular device the sclerosant is stored in a bag within an aerosol canister containing physiologically acceptable gas. The device includes an internal valve arrangement. The valve, which is positioned inside the gas filled canister but outside the bag, facilitates mixing of the gas with the sclerosant contained in the bag in order to produce a microfoam. This bag-on-valve construction is intended to impart a degree of orientation-dependence to the device, when compared with a similar device in which the polidocanol solution is free liquid in the bottom of the canister. The potential problem with long-term storage is not addressed.
Co-pending application WO 02/41872-A1 (BTG International Limited) presents a different method and apparatus for the production of a foam suitable for scleropathy. The sclerosant liquid and the oxygen-rich physiologically acceptable blood dispersible gas are stored in separate containers until immediately prior to use, when the blood-dispersible gas is introduced into the container holding the sclerosant liquid until pressure equilibrium is reached between the two connected containers. The mixture of blood-dispersible gas and sclerosant liquid is then released, the components of the mixture interacting upon release of the mixture to form a sclerosing foam. The sclerosant container used is generally a conventional aerosol canister, which has been modified to make it suitable for use in storing and dispensing a sterile sclerosing agent. This apparatus and method produce an excellent sclerosing microfoam, and the use of separate containers for the gas and the sclerosant advantageously avoids the problem of storing the sclerosing fluid, for example, aqueous polidocanol, in the presence of oxygen.
The present inventors have also discovered a number of potential problems with the commercial manufacture of the prior art systems. These relate largely to the difficulties in sterilising and storing aqueous sclerosant solutions, and to the costs of the alternative of aseptic-filled manufacturing techniques. For example, terminal heat sterilisation by autoclaving is the preferred method of ensuring that the aqueous sclerosant is sterile during storage and prior to administration to the patient. WO 00/72821-A1 discloses the use of robust, epoxy coated aluminium aerosol canisters, which have been found to be resistant to the action of polidocanol and oxygen during storage, and to sterilisation by gamma irradiation.
The present inventors have discovered that the heat sterilisation of aqueous polidocanol solution is acceptable in a glass vessel with an inert atmosphere in the container, but may be troublesome in standard aerosol canisters. There is, therefore, a need for a different method and device suitable for the storage of aqueous sclerosant solutions and for the production of a foam suitable for scleropathy.
However, the container that stores the liquid sclerosant is rigid-walled in the prior art, and therefore of fixed internal volume. There are conflicting requirements for this container, as during storage the internal volume of the container holding the sclerosant liquid is best minimised to reduce the amount of inert or compatible gas that is needed during storage (for example nitrogen or carbon dioxide) which would be included in the final, oxygen-rich gas mix after charging, whereas in the final pressurised container, the propellant for the ejection of foam is a compressed gas mix, and a significant container internal volume is required to keep pressure decay at a minimum to preserve foam density and foam ejection rate between specified limits during the ejection of foam from the container. The have also discovered that rigid-walled containers used in the prior art, because they are of fixed internal volume do not meet the conflicting requirements of fixed internal volume.